CN106619503B - A kind of Rhein amide derivatives nano suspension and its preparation method and application - Google Patents
A kind of Rhein amide derivatives nano suspension and its preparation method and application Download PDFInfo
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- CN106619503B CN106619503B CN201610846220.5A CN201610846220A CN106619503B CN 106619503 B CN106619503 B CN 106619503B CN 201610846220 A CN201610846220 A CN 201610846220A CN 106619503 B CN106619503 B CN 106619503B
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- 230000012202 endocytosis Effects 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000003513 sheep sorrel Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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Abstract
The invention discloses a kind of Rhein amide derivatives nano suspensions and its preparation method and application.Since Rhein water solubility is low, poor bioavailability significantly limits the exploitation and clinical application of Rhein.The present invention proposes a kind of preparation method of simpler, quick, high yield Rhein amide derivatives nano suspension to Rhein amide derivatives: Rhein amide derivatives being dissolved in organic solvent, as oily phase；Stabilizer is soluble in water, as water phase；Water phase is placed in ice-water bath, under stirring, oily phase is added dropwise, continues to stir 30-40min after dispersion completely, revolving removes organic solvent, under the conditions of 20000rpm, with high-speed shearing machine continuous shear stress, stands, after defoaming, obtains thick suspension；Thick suspension is handled through ultrasonic method and/or high pressure homogenization method, obtains Rhein amide derivatives nano suspension.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, more particularly to a kind of Rhein amide derivatives nano suspension and its
Preparation method and application.
Background technique
Rheum officinale derives from polygonaceae herbaceos perennial sorrel (Rheum palmatum L.), Rheum tanguticum Maxim
The dry root and root of (R.tanguticum Maxim.ex Balf.) or Rheum officinale (Rheum officinale Baill.)
Stem.First recorded in Shennong's Herbal, taste bitter and cold, returns spleen, stomach, large intestine, liver, the heart channel of Hang-Shaoyin have by addiction dysmenorrhea, and expel the heat-evil logical intestines,
The effect of removing pattogenic heat from the blood and toxic material from the body.Clinic is usually used in cholecystitis, hepatitis, diabetes, nephrosis, chronic renal failure and constipation and other diseases
Treatment.The main pharmacological components of rheum officinale are anthraquinone derivative (content accounts for about 3%~5%) and a small amount of dianthrone analog derivative.
Wherein, sequestered anthraquinone is the main antimicrobial component of rheum officinale, and combined anthraquinone is then that rheum officinale mainly rushes down lower ingredient.Modern study
Show that sequestered anthraquinone analog compound has anti-tumor activity.
Principle active component of the Rhein (Rhein, RH) as Chinese herb rhubarb, Chinese medicine aloe etc. belongs to single anthracene core class 1,8-
Dihydroxy-anthracene quinone derivative, a large amount of pharmaceutical research the result shows that, Rhein is in hypoglycemic fat-regulating, antitumor, antiviral, anti-fibre
Dimensionization, antibacterial, liver protection etc. are many-sided to have extensive pharmacological activity, especially in treatment osteoarthritis, diabetes, nephrosis and association
There is therapeutic effect outstanding with anti-tumor aspect, is one of Recent study hot spot.But since its water solubility is low, biological utilisation
It is poor to spend, and significantly limits the exploitation and clinical application of Rhein.Only structure is carried out to Rhein in the prior art to change
It makes, without the further investigation of related preparations.
Nano suspension is a kind of novel nano drug delivery system to grow up at the end of the 20th century, due to not using additive,
Nano suspension can be to avoid being eliminated and toxicity problem caused by assembling in vivo by additive.With traditional small molecule anti-cancer drug
Object is compared, and nano suspension is with following outstanding advantages: 1) drug can be made to have controlled-release effect, be able to extend drug in vivo
Half-life period；2) drug can be made to have the effect of targeting conveying, nano suspension passes through its high-permeability and retention effect (EPR),
Targeted drug delivery to tumor locus to reduce the toxic side effect of its normal tissue, can be improved the biology benefit of drug
Expenditure；3) dissolubility of hydrophobic anticancer drug can be improved by chemical bond key and the modes such as adsorption or physics solubilising,
It is effectively improved its administration mode；4) tumour cell can be entered by endocytosis mode, and solve that epithelium and endothelium is effectively overcome to transport
The problem of defeated obstacle；5) the effects of a variety of drugs can be conveyed simultaneously, realize and be administered in combination, enhance drugs against tumor；6) can pass through
It contains or is connect with imaging agent, make drug conveying visualization, convenient for real-time tracking research drug conveying in vivo and discharged
Journey.
Therefore, in order to further increase the bioavilability of former compound, while there is slow releasing function, develops Rhein acyl
The novel form of amine derivant with significant importance.
Summary of the invention
It is an object of the invention to provide a kind of simpler, quick, high yield Rhein amide derivatives are mixed
The preparation method of suspension.
The second purpose of the invention is to provide the application of Rhein amide derivatives nano suspension clinically.
The technical solution adopted by the present invention is that: a kind of Rhein amide derivatives nano suspension, preparation method include
Following steps:
1) Rhein amide derivatives are dissolved in organic solvent, as oily phase；Stabilizer is soluble in water, as water
Phase；
2) water phase is placed in ice-water bath, under stirring, oily phase is added dropwise, continues to stir 30-40min after dispersion completely,
Revolving removes organic solvent, under the conditions of 20000rpm, with high-speed shearing machine continuous shear stress, stands, after defoaming, is slightly suspended
Agent；
3) thick suspension is handled through ultrasonic method and/or high pressure homogenization method, obtains Rhein amide derivatives nanometer suspension
Agent.
A kind of above-mentioned Rhein amide derivatives nano suspension, the Rhein amide derivatives have logical
The structure of formula (I),
Wherein, R is l-Alanine, Valine, L-Leu, l-Isoleucine, L-PROLINE, L-phenylalanine, L-
Tryptophan, L-Methionine, L- glycine, Serine, L-threonine, L-cysteine, l-tyrosine, altheine, L-
Glutamine, L-lysine, L-Histidine, L-Aspartic acid, Pidolidone.Preferably, R is l-Isoleucine or L- phenylpropyl alcohol ammonia
Acid.
A kind of above-mentioned Rhein amide derivatives nano suspension, by weight, Rhein amide derivatives: steady
Determine agent=1:0.3-1.Preferably, Rhein amide derivatives: stabilizer=1:1.
A kind of above-mentioned Rhein amide derivatives nano suspension, the organic solvent are selected from methanol, anhydrous second
The mixing of one of alcohol, ethyl acetate, chloroform, acetone, DMSO or DMF or two kinds or more.Preferably, organic solvent is first
Alcohol, dosage control exist, 2~8mL/50 milligrams of Rhein amide derivatives, it is furthermore preferred that methanol usage is 4mL.
A kind of above-mentioned Rhein amide derivatives nano suspension, the stabilizer are selected from PLURONICS F87
(F68), one of lecithin (LC), povidone (PVP) or hydroxypropyl cellulose (HPC) or two kinds or more of mixing.It is preferred that
, stabilizer is, by weight, PLURONICS F87: lecithin=1:1 mixing.
A kind of above-mentioned Rhein amide derivatives nano suspension is mutually at the uniform velocity added dropwise oily in water phase, at the uniform velocity
Refer to 0.5~2.0mL/min, preferably 1.0mL/min.
Above-mentioned freeze drying protectant is selected from the group of one or more of mannitol, lactose, sucrose, trehalose, maltose
It closes, preferably mannitol.Its dosage is controlled 1~10%, preferably 5%.
A kind of above-mentioned Rhein amide derivatives nano suspension, the ultrasonic method is: thick suspension is shifted
Into ultrasonic cell disruptor, under 135~360W of ultrasonic power, the Probe Ultrasonic Searching time is controlled in 2~8min.Preferably,
Ultrasonic power is 315W, and the Probe Ultrasonic Searching time controls in 4min
A kind of above-mentioned Rhein amide derivatives nano suspension, the high pressure homogenization method is: by thick suspension
It is transferred in high pressure microfluidizer, after 4660psi homogeneous 3 times, homogeneous 5~25 times under 6990~16310psi pressure.It is preferred that
, after 4660psi homogeneous 3 times, homogeneous 20 times under 11650psi pressure.
The present invention is when handling thick suspension, selection ultrasonic method or high pressure homogenization method that can be single, can also be with
The two uses simultaneously.
In order to facilitate long term storage and animal experiment, a kind of above-mentioned Rhein amide derivatives nano suspension, packet
Step of freeze drying is included, the step of freeze drying is: in Rhein amide derivatives nano suspension, freeze drying protectant is added,
It after being completely dissolved, is taken out after pre-freeze 48h under the conditions of -80 DEG C, is put into freeze drier and is lyophilized, obtained nanometer suspension freeze-dried
Powder.This freeze-dried powder, which can be further processed, is prepared into capsule, tablet, injection etc..
A kind of above-mentioned Rhein amide derivatives nano suspension, the freeze drying protectant are selected from mannitol, cream
The combination of one of sugar, sucrose, trehalose, maltose or two kinds or more.
Application of the Rhein amide derivatives nano suspension provided by the invention in preparation treatment anti-tumor drug.
The synthetic method of Rhein amide derivatives provided by the invention is as follows:
1) synthesis of rheum officinale amic acid methyl esters: weighing Rhein (RH) in eggplant-shape bottle, and excessive carboxy protective is added
Amino acid methyl ester hydrochloride (or diethyl ester hydrochloride), amino acid methyl ester hydrochloride (or the diethyl ester hydrochloride of RH and carboxy protective
Salt) molar ratio control between 1:1~1:5, be placed in magnetic agitation, continuously add 1- ethyl-(3- dimethylaminopropyl)
Phosphinylidyne diimmonium salt hydrochlorate (EDCHCl), 1- hydroxy benzo triazole (HOBt) are added triethylamine along wall, dichloromethane are added
Alkane.Reaction is stirred at room temperature, TLC (chloroform makees solvent) monitors reaction process.Above-mentioned reaction solution is poured into liquid separation by 6h end of reaction
In funnel, it is slowly added to the extraction of 18% hydrochloric acid solution three times, collects dichloromethane layer liquid, methylene chloride is mutually with saturation NaHCO3
Aqueous solution is extracted to that upper layer is colourless, and methylene chloride phase anhydrous sodium sulfate dries, filters repeatedly, filtrate decompression be concentrated by evaporation to get
Rheum officinale amic acid methyl esters.
2) it is molten that appropriate 1M NaOH the synthesis of Rhein amide derivatives: is added in Xiang Shangshu rheum officinale amic acid methyl esters
Liquid, after ultrasonic dissolution, 45 DEG C are stirred to react, TLC (chloroform makees solvent) monitoring reaction, and completely, filter is collected in filtering for 1h hydrolysis
Liquid.It places reaction liquid into 0 DEG C of ice-water bath, 10% hydrochloric acid solution is added dropwise under stirring, adjust pH 1~2, stand overnight, analyse
Solid out filters, and collects filter cake, dry to get Rhein amide derivatives.
The present invention determines each compound in different organic solvents and different pH buffers using efficient liquid phase (HPLC) method
In solubility (being shown in Table 1, table 2), and the Determination of oil-water partition coefficient (being shown in Table 3) in difference pH buffer, the results showed that have part
The water-soluble and fat-soluble of compound is significantly improved compared with RH, and Determination of oil-water partition coefficient also increases；It (is shown in Table using mtt assay
4) as a result each Compound ira vitro activity of Preliminary Determination proves that part of compounds has apparent Inhibit proliferaton to hepatoma Hep G 2 cells
Effect；Internal pharmacokinetic (see Fig. 1) the result shows that the blood concentration of partial derivatives relatively have with the RH of mole it is bright
It is aobvious to improve.The above index of each compound is comprehensively compared, preferably out two kinds optimal compound rheum officinale acyl isoleucine (Rhein-
Isoleucine, RH-Ile) and rheum officinale acyl phenylalanine (Rhein-phenylalanine, RH-Phe), it is furtherd investigate.
Equilbrium solubility (Mean ± SD, n=3) of 1 part of compounds of table in different solvents
Equilbrium solubility (Mean ± SD, n=3) of 2 part of compounds of table in different pH buffers
Apparent partition coefficients (Mean ± SD, n=3) of 3 part of compounds of table in different solvents
Inhibited proliferation of 4 part of compounds of table to hepatoma Hep G 2 cells
Note: "-" indicates that low concentration promotes, and high concentration inhibits, and significantly facilitates proliferation function.
The invention has the advantages that it is of the invention, it is prepared for a series of Rhein amide derivatives nano suspensions, preparation side
Method simple possible, products collection efficiency and purity are higher.The present invention has carried out selection to preparation method and has compared, and prepared work to influence
An important factor for skill, is investigated, and is that index determines optimal prescription work with partial size, Zeta potential and polydispersity coefficient (PDI)
Skill, by comparing the pharmacokinetic parameters of preparation and former compound, the results showed that, after being prepared into preparation, RH-Ile and RH-Phe's
Bioavilability has been respectively increased 2 times and 3.5 times or so, and half-life period extends 3.45h and 6.37h respectively, has slow release effect.
The structure of modification product of Rhein has been prepared into nano suspension for the first time by the present invention, and has been inquired into internal after being prepared into preparation
Pharmacokinetics, the clinical application that product is transformed for Rhein class formation are laid a good foundation.
Detailed description of the invention
Fig. 1: Oral Administration in Rats gives mean blood plasma concentration-time graph (n=6) after RH and Rhein amide derivatives.
Fig. 2: partial size and Zeta potential figure.
Wherein, A:RH-Ile-NS grain-size graph；The Zeta potential figure of B:RH-Ile-NS；C:RH-Ile-NS freeze-dried powder partial size
Figure；D:RH-Ile-NS freeze-dried powder Zeta potential figure.
Fig. 3: partial size and Zeta potential figure.
Wherein, A:RH-Phe-NS grain-size graph；The Zeta potential figure of B:RH-Phe-NS；C:RH-Phe-NS freeze-dried powder partial size
Figure；D:RH-Phe-NS freeze-dried powder Zeta potential figure.
Fig. 4: nanosuspension frozen powder TEM figure.
Wherein, A:RH-Ile-NS；B:RH-Phe-NS.
Fig. 5: differential calorimetric scan profiling results.
Fig. 6: Oral Administration in Rats gives mean blood plasma concentration-time graph (n=6) after RH-Ile-NS.
Fig. 7: Oral Administration in Rats gives mean blood plasma concentration-time graph (n=6) after RH-Phe-NS.
Specific embodiment
The preparation of rheum officinale acyl phenylalanine (Rhein-phenylalanine, RH-Phe): weigh RH 1.76mmol in
In 100mL eggplant-shape bottle, 3.52mmol L-phenylalanine methyl ester hydrochloride is added, is placed in magnetic agitation, continuously adds EDC
HCl 2.50mmol, HOBt 1.85mmol is added triethylamine 1mL along wall, 10~20mL of methylene chloride is added.It is stirred at room temperature anti-
It answers, TLC (chloroform makees solvent) monitors reaction process.6h end of reaction pours into above-mentioned reaction solution in separatory funnel, slowly adds
Enter the extraction of 18% hydrochloric acid solution three times, collects dichloromethane layer liquid, methylene chloride is mutually with saturation NaHCO3Aqueous solution extracts repeatedly
Take colourless to upper layer, methylene chloride phase anhydrous sodium sulfate dries, filters, and filtrate decompression is concentrated by evaporation to get rheum officinale acyl phenylpropyl alcohol ammonia
Sour methyl esters.It is added appropriate 1M NaOH solution into above-mentioned rheum officinale acyl phenyalanine methyl ester, after ultrasonic dissolution, 45 DEG C are stirred to react,
TLC (chloroform makees solvent) monitoring reaction, completely, filtrate is collected in filtering for 1h hydrolysis.It places reaction liquid into 0 DEG C of ice-water bath, stirs
It mixes down and 10% hydrochloric acid solution is added dropwise, adjust pH 1~2, stand overnight, solid is precipitated, filter, collect filter cake, it is dry, i.e.,
Obtain rheum officinale acyl phenylalanine.
RH-Phe, C24H17NO7, yellowish-brown pulverulent solids, yield 76%.1H-NMR (400MHz, DMSO-d6/ TMS): δ
11.98 (2H, d, J=4.9Hz, 1-OH and 8-OH), the 9.20 (- H of 1H, d, J=8.2Hz, 2 '), 8.06 (1H, s, 4-H), 7.77-
7.67 (3H, m, 5,6,7-H), 7.36-7.27 (5H, m, 7 ', 8 ', 9 ', 10 ', 11 '-H), 7.18 (1H, d, J=7.2Hz, 2-
H), the 4.71-4.64 (- H of 1H, s, 3 '), the 3.26-3.11 (- H of 2H, m, 5 ').IR (KBr): 3304.06 (association OH), 1728.22
(s, COOH), 1676.14 (amidocarbonylations), 1635.64 (quinone carbonyls), 1610.56,1564.27,1475.54,1452.40,
1373.32,1298.09,1261.45,1201.65,1157.29,748.38,717.52,704.02 (phenyl ring) cm-1。MS(ESI)
M/z (%): 432.1 [M+H]+, 454.0 [M+Na]+, show that compound molecular weight is 431, be consistent with RH-Phe molecular weight.
The preparation of rheum officinale acyl isoleucine (Rhein-isoleucine, RH-Ile): RH 1.76mmol is weighed in 100mL
In eggplant-shape bottle, 3.52mmol l-Isoleucine methyl ester hydrochloride is added, is placed in magnetic agitation, continuously adds EDC
HCl2.50mmol, HOBt 1.85mmol are added triethylamine 1mL along wall, 10~20mL of methylene chloride are added.It is stirred at room temperature anti-
It answers, TLC (chloroform makees solvent) monitors reaction process.6h end of reaction pours into above-mentioned reaction solution in separatory funnel, slowly adds
Enter the extraction of 18% hydrochloric acid solution three times, collects dichloromethane layer liquid, methylene chloride is mutually with saturation NaHCO3Aqueous solution extracts repeatedly
Take colourless to upper layer, methylene chloride phase anhydrous sodium sulfate dries, filters, and filtrate decompression is concentrated by evaporation to get the different bright ammonia of rheum officinale acyl
Sour methyl esters.It is added appropriate 1M NaOH solution into above-mentioned rheum officinale acyl Isoleucine methyl ester, after ultrasonic dissolution, 45 DEG C are stirred to react,
TLC (chloroform makees solvent) monitoring reaction, completely, filtrate is collected in filtering for 1h hydrolysis.It places reaction liquid into 0 DEG C of ice-water bath, stirs
It mixes down and 10% hydrochloric acid solution is added dropwise, adjust pH 1~2, stand overnight, solid is precipitated, filter, collect filter cake, it is dry, i.e.,
Obtain rheum officinale acyl isoleucine.
RH-Ile, C21H19NO7, yellow powdery solid, yield 78%.1H-NMR (400MHz, DMSO-d6/ TMS): δ
The 12.72 (- COOH of 1H, s, 4 '), 11.94 (2H, s, 1-OH and 8-OH), the 9.00 (- H of 1H, d, J=7.9Hz, 2 '), 8.16 (1H,
S, 4-H), 7.85-7.77 (3H, m, 5,6,7-H), 7.43 (1H, d, J=9.4Hz, 2-H), 4.36 (1H, t, J=7.5Hz, 3 '-
H), the 1.99 (- H of 1H, s, 5 '), the 1.58-1.24 (- H of 2H, m, 7 '), the 1.03-0.79 (- H of 6H, m, 6 ' and 8 '-H).IR (KBr):
3421.72 (wide, w), 3288.63 (association OH), 1718.58 (s, COOH), 1674.21 (amidocarbonylations), 1645.28 (quinone carbonyls
Base), 1629.85,1533.41,1477.47,1454.33,1379.10,1276.88,1201.65,1157.29,752.24,
(704.02 phenyl ring) cm-1.MS (ESI) m/z (%): 398.1 [M+H]+, 420.1 [M+Na]+, show that compound molecular weight is
397, it is consistent with RH-Ile molecular weight.
The influence of 1 ultrasonic method of embodiment and high pressure homogenization method to nano suspension
(1) rheum officinale acyl isoleucine nano suspension (RH-Ile-NS)
1) precipitating-ultrasonic method (Precipitation-ultrasonic method, PU method): RH-Ile is weighed
50mg uses methanol 4mL dissolution mutually spare as oil.Weigh PLURONICS F87 (Poloxamer, F68) 25mg, lecithin
In 100mL beaker pure water 40mL is added, ultrasonic dissolution is as water phase in (Lecithin, LC) 25mg.Water phase is placed in ice water
In bath, at the uniform velocity oily phase is added dropwise in (1.0mL/min) while stirring, continues to stir 30min after dispersion completely, revolving removes first
Alcohol.Under the conditions of 20000rpm, 3min is sheared with high-speed shearing machine, 10min is stood, after defoaming, is transferred to supersonic cell powder
In broken machine, under the conditions of ultrasonic power 315W, Probe Ultrasonic Searching 4min (pulse opens 2s and stops 2s) to get.
2) precipitating-high pressure homogenization method (High pressure homogenization method, HPH method): claim
RH-Ile50mg is taken, uses methanol 4mL dissolution mutually spare as oil.F68 25mg is weighed, LC 25mg is added in 100mL beaker
Pure water 40mL, ultrasonic dissolution is as water phase.Water phase is placed in ice-water bath, at the uniform velocity (1.0mL/min) adds dropwise while stirring
Enter oily phase, continues to stir 30min after dispersion completely, revolving removes methanol.Under the conditions of 20000rpm, sheared with high-speed shearing machine
3min stands 10min, after defoaming, is transferred in high pressure microfluidizer, 4660psi homogeneous 3 times, 11650psi homogeneous 20 times, i.e.,
?.
(2) rheum officinale acyl phenylalanine nano suspension (RH-Phe-NS)
1) precipitating-ultrasonic method (Precipitation-ultrasonic method, PU method): method is the same as rheum officinale acyl
Precipitating-ultrasonic method of isoleucine nano suspension.
2) precipitating-high pressure homogenization method (High pressure homogenization method, HPH method): side
Precipitating-high pressure homogenization method of the method with rheum officinale acyl isoleucine nano suspension.
(3) partial size and Zeta potential are measured
Partial size and Zeta potential distribution using laser particle analyzer measurement RH-Ile-NS and RH-Phe-NS, as a result such as table 5.
The influence (Mean ± SD, n=3) of 5 ultrasonic method of table and high pressure homogenization method to partial size, Zeta potential and PDI
By table 5 as it can be seen that precipitating-high pressure homogenization method preparation nano suspension partial size is smaller and more stable, uniform therefore excellent
Select high pressure homogenization method.
Influence of 2 homogenization pressure of embodiment to nano suspension
RH-Ile and RH-Phe 50mg is weighed respectively, uses methanol 4mL dissolution mutually spare as oil.Weigh F68 25mg, LC
In 100mL beaker pure water 40mL is added, ultrasonic dissolution is as water phase in 25mg.Water phase is placed in ice-water bath, while stirring
Oily phase is at the uniform velocity added dropwise, continues to stir 30min after dispersion completely, revolving removes methanol.Under the conditions of 20000rpm, with high speed
Cutter shears 3min, stands 10min, after defoaming, is transferred in high pressure microfluidizer, after 4660psi homogeneous 3 times, respectively at
Homogeneous 20 times under the conditions of 6990psi, 9320psi, 11650psi, 13980psi, 16310psi, respectively obtain RH-Ile-NS and
RH-Phe-NS.Partial size and Zeta potential are measured, as a result such as table 6 and table 7.
Influence (Mean ± SD, n=3) of 6 homogenization pressure of table to RH-Ile-NS partial size, Zeta potential and PDI
Influence (Mean ± SD, n=3) of 7 homogenization pressure of table to RH-Phe-NS partial size, Zeta potential and PDI
By table 6 and table 7 as it can be seen that for RH-Ile-NS, with the increase of homogenization pressure, Zeta potential has almost no change,
Illustrate that Zeta potential is unrelated with homogenization pressure, and partial size and PDI then show decline trend, in 13980psi, partial size is minimum,
When pressure continues growing, partial size becomes larger instead.As PDI<0.3, it is believed that partial size is relatively uniform, when homogenization pressure>=
When 11650psi, PDI meets the requirements, wherein for homogenization pressure in 16310psi, PDI is minimum, and studies discovery homogenization pressure
In 11650psi and 13980psi, partial size is not much different, it is contemplated that the loss of instrument, it is preferable that homogenization pressure 11650psi.It is right
In RH-Phe-NS, as homogenization pressure increases, for Zeta potential also without significant change, partial size shows decline trend, homogeneous
Partial size is minimum when pressure 16310psi, but studies discovery PDI and only meet the requirements in homogenization pressure 11650psi, this may be
When excessive due to homogenization pressure, will lead to small particle size fraction in system becomes smaller, therefore PDI becomes larger, system partial size difference compared with
Greatly, for the above reasons, final choice homogenization pressure 11650psi.
Influence of 3 homogenization cycles of embodiment to suspension
RH-Ile and RH-Phe 50mg is weighed respectively, uses methanol 4mL dissolution mutually spare as oil.F68 25mg separately is weighed,
In 100mL beaker pure water 40mL is added, ultrasonic dissolution is as water phase in LC 25mg.Water phase is placed in ice-water bath, while stirring
It mixes side and oily phase is at the uniform velocity added dropwise, continue to stir 30min after dispersion completely, revolving removes methanol.Under the conditions of 20000rpm, use
High-speed shearing machine shears 3min, after standing 10min defoaming, is transferred in high pressure microjet, after 4660psi homogeneous 3 times, in
Homogeneous is distinguished under 11650psi pressure 5 times, 10 times, 15 times, 20 times, 25 times, respectively obtain RH-Ile-NS and RH-Phe-NS.It surveys
Partial size and Zeta potential are determined, as a result such as table 8 and table 9.
Influence (Mean ± SD, n=3) of 8 homogenization cycles of table to RH-Ile-NS partial size, Zeta potential and PDI
Influence (Mean ± SD, n=3) of 9 homogenization cycles of table to RH-Phe-NS partial size, Zeta potential and PDI
By table 8 and table 9 as it can be seen that for RH-Ile-NS, with the increase of homogenization cycles, the partial size of preparation shows first to subtract
The trend increased after small, at homogeneous 20 times, partial size is minimum, and also without significant change, PDI then shows to successively decrease Zeta potential
Trend, PDI is minimum at homogeneous 25 times, but at homogenization cycles >=20 time, PDI is respectively less than 0.3, comprehensively considers, preferably homogeneous 20
It is secondary.For RH-Phe-NS, as homogenization cycles increase, partial size equally shows the trend for first reducing and increasing afterwards, the grain at 20 times
Diameter is minimum, and Zeta potential does not have significant change, but overall smaller than the Zeta potential of RH-Ile-NS, shows the body of RH-Phe-NS
System may be more stable.PDI increases afterwards as homogenization cycles increase first reduces, and reaches minimum value at homogeneous 20 times, comprehensively considers,
It preferably selects homogeneous 20 times.
Influence of 4 stabilizer of embodiment to suspension
RH-Ile and RH-Phe 50mg is weighed respectively, uses methanol 4mL dissolution mutually spare as oil.Claim by table 10 and table 11
It takes stabilizer 50mg (two kinds of stabilizers then each 25mg) in 100mL beaker, pure water 40mL is added, ultrasonic dissolution is as water
Phase.Water phase is placed in ice-water bath, oily phase is at the uniform velocity added dropwise while stirring, continues to stir 30min after dispersion completely, revolving is removed
Remove methanol.Under the conditions of 20000rpm, 3min is sheared with high-speed shearing machine, after standing 10min defoaming, is transferred to high pressure microjet
In machine, after 4660psi homogeneous 3 times, homogeneous 20 times are distinguished under 11650psi pressure to get RH-Ile-NS and RH-Phe-NS.
Partial size and Zeta potential are measured, as a result such as table 10 and table 11.
10 RH-Ile-NS prescription of table investigates (Mean ± SD, n=3)
11 RH-Phe-NS prescription of table investigates (Mean ± SD, n=3)
By table 10 and table 11 as it can be seen that the nano suspension partial size being mixed to prepare using two kinds of stabilizers is relatively smaller, more surely
It is fixed.For RH-Ile-NS, while when selecting F68 and LC as stabilizer, obtained nano suspension partial size is minimum,
Zeta potential is relatively stable, and PDI < 0.3 meets the requirements；For RH-Phe-NS, partial size is whole smaller relative to RH-Ile-NS,
Partial size equally shows minimum when selecting F68 and LC simultaneously, and Zeta potential absolute value is bigger compared to RH-Ile-NS, indicates body
Be it is more more stable, PDI also corresponds to require, thus select F68 and LC as stabilizer.
Influence of the ratio of embodiment 5 F68 and LC to suspension
RH-Ile and RH-Phe 50mg is weighed respectively, uses methanol 4mL dissolution mutually spare as oil.Claim by table 12 and table 13
It takes F68 and LC in 100mL beaker, pure water 40mL is added, ultrasonic dissolution is as water phase.Water phase is placed in ice-water bath, side
Oily phase is at the uniform velocity added dropwise in stirring side, continues to stir 30min after dispersion completely, revolving removes methanol.Under the conditions of 20000rpm,
3min is sheared with high-speed shearing machine, after standing 10min defoaming, is transferred in high pressure microjet, after 4660psi homogeneous 3 times, in
Homogeneous 20 times are distinguished under 11650psi pressure to get RH-Ile-NS and RH-Phe-NS.Partial size and Zeta potential are measured, as a result such as
12 and table 13.
12 RH-Ile-NS prescription of table investigates (Mean ± SD, n=3)
13 RH-Phe-NS prescription of table investigates (Mean ± SD, n=3)
By table 12 and table 13 as it can be seen that having investigated the dosage and the two of stabilizer F68 and LC within the scope of 15~30mg respectively
Ratio, as a result, it has been found that, influence of the dosage of the amount ratio F68 of LC to partial size is larger, this may be because LC stabilization
It acts on stronger, compound particles can be made dispersedly more evenly to stablize.Studies have shown that the absolute value when Zeta potential is greater than
When 20mV, nano suspension has preferable stability.When F68 and LC are 25mg, partial size is minimum, and Zeta potential conforms to
It asks, and PDI is also respectively less than 0.3, therefore final choice F68 25mg and LC 25mg are as stabilizer.
6 rheum officinale acyl isoleucine nanosuspension frozen powder of embodiment and rheum officinale acyl phenylalanine nanosuspension frozen powder
Preparation
Appropriate mannitol is weighed in cillin bottle, is separately added into 2mL RH-Ile-NS and RH-Phe-NS, it is light to shake to sweet dew
After alcohol is completely dissolved, it is put into ultra low temperature freezer, is taken out after pre-freeze 48h under the conditions of -80 DEG C, is put into freeze drier and is lyophilized,
Appearance, redispersibility and partial size by investigating freeze-dried powder determine final prescription, and change of size situation is shown in after freeze-dried powder redissolution
Table 14.
Influence (Mean ± SD, n=3) of 14 freeze drying protectant of table to partial size
After table 14 shows that not adding freeze drying protectant is directly lyophilized, preparation is tightly attached in the bottle wall of XiLin, and it is super that pure water is added
Sound redissolves, and can not be completely dispersed, partial size is also maximum；After adding the freeze-drying of 2.5% mannitol, sample appearance has atrophy, and part is tied
Block is added pure water ultrasound and redissolves, can be uniformly dispersed, but change of size is larger；After the freeze-drying of 5% mannitol is added, sample matter
Ground is loose, and color is uniform, and ultrasound a moment can be uniformly dispersed after pure water is added, and change of size is smaller after measurement is redissolved, and stablizes
Property it is also preferable, therefore select 5% mannitol is added and as freeze drying protectant prepare freeze-dried powder.
Using partial size and Zeta potential distribution before and after the freeze-drying of laser particle analyzer measurement RH-Ile-NS and RH-Phe-NS, survey
Determine result such as Fig. 2 and Fig. 3, the results show that the latter two partial sizes, which are lyophilized, increases by 20~30nm, Zeta potential is then without significant change.
Partial size after being redissolved using transmission electron microscope (TEM) measurement RH-Ile-NS freeze-dried powder and RH-Phe-NS freeze-dried powder, as a result
Such as Fig. 4, the two partial size in 200nm or so, is not much different, and particle is spherical in shape, and each other without being adhered, preparation stability is good
It is good.
F68, LC, mannitol, RH-Ile, RH-Phe, RH-Ile-NS are measured using differential calorimetric scan instrument (DSC) respectively
Freeze-dried powder, RH-Phe-NS freeze-dried powder and the respective physical mixture of the two, set temperature is with the speed of 10 DEG C/min from 25 DEG C
300 DEG C are raised to, measurement result is shown in Fig. 5.The results show that appearance, F68 do not have endothermic peak, frozen-dried protective to auxiliary material LC at 55.67 DEG C
There is endothermic peak at 169.5 DEG C in agent mannitol, the endothermic peak of RH-Ile at 201.33 DEG C, equally in its physical mixture and
It can be seen that the endothermic peak and mannitol of RH-Ile and the endothermic peak of F68 in RH-Ile-NS.There are one in RH-Phe
A 184 DEG C of exothermic peak and 232.33 DEG C of endothermic peak, it is also the same it can be seen that explanation in its physical mixture and preparation
No change has taken place for crystal form after RH-Ile and RH-Phe is prepared into nano suspension, is crystalline.
The Internal pharmacokinetics situation of embodiment 7 RH-Ile-NS and RH-Phe-NS
Selection SD rat is animal pattern, respectively gastric infusion, analyzes Drug-time curve (see Fig. 6, Fig. 7) and pharmacokinetics ginseng
Number, is compared, to study with the rat Internal pharmacokinetics parameter (being shown in Table 15) of RH-Ile suspension and RH-Phe suspension
It is prepared into after nano suspension to the facilitation of the oral absorption of bulk pharmaceutical chemicals.The result shows that prepared by RH-Ile and RH-Phe
After nano suspension, achieved the purpose that it is expected further increase bioavilability, and there is slow release effect, enhance
Drug effect.
15 Oral Administration in Rats of table gives the pharmacokinetic parameters (Mean ± SD, n=6) after Rhein amide derivatives and preparation
The compared with rhein-isoleucine of Note:*P < 0.05 (rhein-phenylalanine)
suspensions
**P<0.01compared with rhein-isoleucine(rhein-phenylalanine)
suspensions。
Claims (4)
1. a kind of preparation method of Rhein amide derivatives nano suspension, which comprises the steps of:
1) Rhein amide derivatives are dissolved in organic solvent, as oily phase；Stabilizer is soluble in water, as water phase；
The stabilizer is PLURONICS F87 by weight: lecithin=1:1 mixing；Rhein amide derivatives: stablize
Agent=1:1；
2) water phase is placed in ice-water bath, under stirring, oily phase is added dropwise, continue to stir 30-40min, revolving after dispersion completely
Organic solvent is removed, under the conditions of 20000rpm, with high-speed shearing machine continuous shear stress, stands, after defoaming, obtains thick suspension；
3) thick suspension is handled through high pressure homogenization method, obtains Rhein amide derivatives nano suspension；The high pressure is equal
Matter method is: thick suspension is transferred in high pressure microfluidizer, after 4660psi homogeneous 3 times, and the homogeneous 20 under 11650psi pressure
It is secondary；
The Rhein amide derivatives have the structure of general formula (I),
Wherein, R is l-Alanine, Valine, L-Leu, l-Isoleucine, L-PROLINE, L-phenylalanine, L- color ammonia
Acid, L-Methionine, L- glycine, Serine, L-threonine, L-cysteine, l-tyrosine, altheine, L- paddy ammonia
Amide, L-lysine, L-Histidine, L-Aspartic acid, Pidolidone.
2. a kind of preparation method of Rhein amide derivatives nano suspension according to claim 1, feature exist
In the organic solvent is selected from one of methanol, dehydrated alcohol, ethyl acetate, chloroform, acetone, DMSO, DMF or two kinds
Above mixing.
3. a kind of preparation method of Rhein amide derivatives nano suspension according to claim 1, feature exist
In, including step of freeze drying, the step of freeze drying is: in Rhein amide derivatives nano suspension, freeze-drying is added and protects
Agent is protected, after being completely dissolved, is taken out after pre-freeze 48h under the conditions of -80 DEG C, is put into freeze drier and is lyophilized, obtain nano suspension
Freeze-dried powder, the freeze drying protectant are 5% mannitol.
4. the Rhein amide derivatives nano suspension prepared according to the method for claim 1 is preparing antineoplastic
Application in object.
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| WO2005085170A1 (en) * | 2004-03-04 | 2005-09-15 | Sosei R&D Ltd. | Ester derivatives of rhein and their therapeutic use |
| CN102232937A (en) * | 2010-04-30 | 2011-11-09 | 天津药物研究院 | Nanometer preparation and preparation method thereof |
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| Title |
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| Novel self-nanoemulsifying self-nanosuspension (SNESNS) for enhancing oral bioavailability of diacerein: Simultaneous portal blood absorption and lymphatic delivery;Hanan M. El-Laithy，等;《International Journal of Pharmaceutics》;20150519;第490卷(第1-2期);第1节以及第3.6节 * |
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